Parkinson""s disease is characterized neuropathologically by degeneration of dopamine neurons in the basal ganglia and neurologically by debilitating tremors, slowness of movement and balance problems. It is estimated that over one million people suffer from Parkinson""s disease. Nearly all patients receive the dopamine precursor levodopa or L-Dopa, often in conjunction with the dopa-decarboxylase inhibitor, carbidopa. L-Dopa adequately controls symptoms of Parkinson""s disease in the early stages of the disease. However, it tends to become less effective after a period which can vary from several months to several years in the course of the disease.
It is believed that the varying effects of L-Dopa in Parkinson""s disease patients is related, at least in part, to the plasma half life of L-Dopa which tends to be very short, in the range of 1 to 3 hours, even when co-administered with carbidopa. In the early stages of the disease, this factor is mitigated by the dopamine storage capacity of the targeted striatal neurons. L-Dopa is taken up and stored by the neurons and is released over time. However, as the disease progresses, dopaminergic neurons degenerate, resulting in decreased dopamine storage capacity. Accordingly, the positive effects of L-Dopa become increasingly related to fluctuations of plasma levels of L-Dopa. In addition, patients tend to develop problems involving gastric emptying and poor intestinal uptake of L-Dopa. Patients exhibit increasingly marked swings in Parkinson""s disease symptoms, ranging from a return to classic Parkinson""s disease symptoms, when plasma levels fall, to the so-called dyskinesis, when plasma levels temporarily rise too high following L-Dopa administration.
As the disease progresses, conventional L-Dopa therapy involves increasingly frequent, but lower dosing schedules. Many patients, for example, receive L-Dopa every two to three hours. It is found, however, that even frequent doses of L-Dopa are inadequate in controlling Parkinson""s disease symptoms. In addition, they inconvenience the patient and often result in non-compliance.
It is also found that even with as many as six to ten L-Dopa doses a day, plasma L-Dopa levels can still fall dangerously low, and the patient can experience very severe Parkinson""s disease symptoms. When this happens, additional L-Dopa is administered as intervention therapy to rapidly increase brain dopamine activity. However, orally administered therapy is associated with an onset period of about 30 to 45 minutes during which the patient suffers unnecessarily. In addition, the combined effects of the intervention therapy, with the regularly scheduled dose can lead to overdosing, which can require hospitalization. For example, subcutaneously administered dopamine receptor agonist (apomorphine), often requiring a peripherally acting dopamine antagonist, for example, domperidone, to control dopamine-induced nausea, is inconvenient and invasive.
Other medical indications involving the central nervous system (CNS) require rapid delivery of a medicament such as but not limited to epilepsy, panic attacks and migraines. For example, about 2 million people in the USA suffer from some form of epilepsy, with the majority receiving at least one of several different anti-seizure medications. The incidence of status epilepticus (the more serious form of epilepsy) is approximately 250,000. A significant number of patients also suffer from so-called xe2x80x9ccluster seizuresxe2x80x9d, wherein an initial seizure forewarns that a series of additional seizures will occur within a relatively short time frame. By some reports, 75% of all patients continue to experience seizures despite taking medication chronically. Poor compliance with the prescribed medications is believed to be a significant (albeit not sole) contributing factor. The importance of controlling or minimizing the frequency and intensity of seizures lies in the fact that incidence of seizures has been correlated with neuronal deficits and is believed to cause loss of neurons in the brain.
Despite chronic treatment, as many as 75% of all patients continue to exhibit periodic seizures. The uncontrolled seizures occur in many forms. In the case of xe2x80x9ccluster seizures,xe2x80x9d one seizure serves notice that a cascade has begun which will lead to a series of seizures before the total episode passes. In certain patients, prior to the onset of a severe seizure, some subjective feeling or sign is detected by the patient (defined as an aura). In both instances, an opportunity exists for these patients to significantly reduce the liability of the seizure through xe2x80x9cself medicationxe2x80x9d. While many patients are instructed to do so, the drugs currently available to permit effective self medication are limited.
Panic attacks purportedly affect at least about 2.5 million people in this country alone. The disorder is characterized by acute episodes of anxiety, leading to difficult breathing, dizziness, heart palpitations and fear of losing control. The disorder is believed to involve a problem with the sympathetic nervous system (involving an exaggerated arousal response, leading to overstimulation of adrenaline release and/or adrenergic neurons). Current pharmacotherapy combines selective serotonin re-uptake inhibitors (SSRIs), or other antidepressant medications, with the concomitant use of benzodiazapines.
A limitation of the pharmacotherapies in current use is the delay in the onset of efficacy at the beginning of treatment. Like treatments for depression, the onset of action of the SSRIs requires weeks rather than days. The resulting requirement for continuous prophylactic treatment can, in turn, lead to significant compliance problems rendering the treatment less effective. Therefore, there is a need for rapid onset therapy at the beginning of treatment to manage the anticipation of the panic attacks, as well as a treatment for aborting any attacks as soon as possible after their occurrence.
A pure vasogenic etiology/pathogenesis for migraine was first proposed in the 1930s; by the 1980s, this was replaced by a neurogenic etiology/pathogenesis, which temporarily won favor among migraine investigators. However, it is now generally recognized that both vasogenic and neurogenic components are involved, interacting as a positive feedback system, with each continuously triggering the other. The major neurotransmitters implicated include serotonin (the site of action of the triptans), substance P (traditionally associated with mediating pain), histamine (traditionally associated with inflammation) and dopamine. The major pathology associated with migraine attacks include an inflammation of the dura, an increase in diameter of meningeal vessels and supersensitivity of the trigeminal cranial nerve, including the branches that enervate the meningeal vessels. The triptans are believed to be effective because they affect both the neural and vascular components of the migraine pathogenic cascade. Migraines include Classic and Common Migraines, Cluster Headaches and Tension Headaches.
Initial studies with sumatriptain showed that, when administered intravenously (IV), a 90% efficacy rate was achieved. However, the efficiency rate is only approximately 60% with the oral form (versus 30% for placebo). The nasal form has proven to be highly variable, requiring training and skill on the part of the patient, which some of the patients do not seem to master. The treatment also induces a bad taste in the mouth which many patients find highly objectionable. There currently exists no clear evidence that any of the recent, more selective 5HT1 receptor agonists are any more efficacious than sumatriptan (which stimulates multiple receptor subtypes; e.g., 1B, 1D, and 1F).
In addition to not providing adequate efficacy, current dosing of triptans have at least two other deficiencies: (1) vasoconstriction of chest and heart muscles, which produces chest tightness and pain in some subjects; this effect also presents an unacceptable risk to hypertensive and other CV patients, for whom the triptans are contraindicated, and (2) the duration of action of current formulations is limited, causing a return of headache in many patients about 4 hours after initial treatment.
Rapid onset of a hypnotic would also be quite desirable and particularly useful in sleep restoration therapy, as middle of night awakening and difficulty in falling asleep again, once awakened, is common in middle aged and aging adults.
Other indications related to the CNS, such as, for example, mania, bipolar disorders, schizophrenia, appetite suppression, motion sickness, nausea and others, as known in the art, also require rapid delivery of a medicament to its site of action.
Therefore, a need exists for methods of delivery of medicaments which are at least as effective as conventional therapies yet minimize or eliminate the above-mentioned problems.
The invention relates to methods of treating disorders of the central nervous system (CNS). More specifically the invention relates to methods of delivering a drug suitable in treating a disorder of the CNS to the pulmonary system and include administering to the respiratory tract of a patient in need of treatment particles comprising an effective amount of the medicament. In one embodiment, the patient is in need of rapid onset of the treatment, for instance in need of rescue therapy; the medicament is released into the patient""s blood stream and reaches the medicament""s site of action in a time interval which is sufficiently short to provide the rescue therapy or rapid treatment onset. In another embodiment, the invention is related to providing ongoing, non-rescue therapy to a patient suffering with a disorder of the CNS.
Disorders of the nervous system include, for example, Parkinson""s disease, epileptic and other seizures, panic attacks, sleep disorders, migraines, attention deficit hyperactivity disorders, Alzheimer""s disease, bipolar disorders, obsessive compulsive disorders and others.
The methods of the invention are particularly useful in the ongoing treatment and for rescue therapy in the course of Parkinson""s disease. The drug or medicament employed in the methods of the invention is a dopamine precursor or a dopamine agonist, for example, levodopa (L-DOPA).
In one embodiment, the invention is related to a method for treating Parkinson""s disease includes administering to the respiratory tract of a patient in need of treatment or rescue therapy a drug for treating Parkinson""s disease, e.g., L-Dopa. The drug is delivered to the pulmonary system, for instance to the alveoli region of the lung. In comparison to oral administration, at least about a two fold dose reduction is employed. Doses generally are between about two times and about ten times less than the dose required with oral administration.
In other embodiments, a method for treating a disorder of the CNS includes administering to the respiratory tract of a patient in need of treatment a drug for treating the disorder. The drug is administered in a dose which is at least about two times less than the dose required with oral administration and is delivered to the pulmonary system.
The doses employed in the invention generally also are at least about two times less than the dose required with routes of administration other than intravenous, such as, for instance, subcutaneous injection, intramuscular injection, intra-peritoneal, buccal, rectal and nasal.
The invention further is related to methods for administering to the pulmonary system a therapeutic dose of the medicament in a small number of steps, and preferably in a single, breath activated step. The invention also is related to methods of delivering a therapeutic dose of a drug to the pulmonary system, in a small number of breaths, and preferably in a single breath. The methods include administering particles from a receptacle which has a mass of particles, to a subject""s respiratory tract. Preferably, the receptacle has a volume of at least about 0.37 cm3 and can have a design suitable for use in a dry powder inhaler. Larger receptacles having a volume of at least about 0.48 cm3, 0.67 cm3 or 0.95 cm3 also can be employed. The receptacle can be held in a single dose breath activated dry powder inhaler.
In one embodiment of the invention, the particles deliver at least about 10 milligrams (mg) of the drug. In other embodiments, the particles deliver at least about 15, 20, 25, 30 milligrams of drug. Higher amounts can also be delivered, for example the particles can deliver at least about 35, 40 or 50 milligrams of drug.
The invention also is related to methods for the efficient delivery of particles to the pulmonary system. In one embodiment, the invention is related to delivering to the pulmonary system particles that represent at least about 70% and preferably at least about 80% of the nominal powder dose. In another embodiment of the invention, a method of delivering a medicament to the pulmonary system, in a single, breath-activated step, includes administering particles, from a receptacle which has a mass of particles, to the respiratory tract of a subject, wherein at least 50% of the mass of particles is delivered.
Preferably, administration to the respiratory tract is by a dry powder inhaler or by a metered dose inhaler. The particles of the invention also can be employed in compositions suitable for delivery to the pulmonary system such as known in the art.
In one embodiment, particles employed in the method of the invention are particles suitable for delivering a medicament to the pulmonary system and in particular to the alveoli or the deep lung. In a preferred embodiment, the particles have a tap density which is less than 0.4 g/cm3. In another preferred embodiment, the particles have a geometric diameter, of at least 5 xcexcm (microns), preferably between about 5 xcexcm and 30 xcexcm. In yet another preferred embodiment, the particles have an aerodynamic diameter between about 1 xcexcm and about 5 xcexcm. In another embodiment, the particles have a mass median geometric diameter (MMGD) larger than 5 xcexcm, preferably around about 10 xcexcm or larger. In yet another embodiment, the particles have a mass median aerodynamic diameter (MMAD) ranging from about 1 xcexcm to about 5 xcexcm. In a preferred embodiment, the particles have an MMAD ranging from about 1 xcexcm tobout 3 xcexcm.
Particles can consist of the medicament or can further include one or more additional components. Rapid release of the medicament into the blood stream and its delivery to its site of action, for example, the central nervous system, is preferred. In one embodiment of the invention, the particles include a material which enhances the release kinetics of the medicament. Examples of suitable such materials include, but are not limited to, certain phospholipids, amino acids, carboxylate moieties combined with salts of multivalent metals and others.
In a preferred embodiment, the energy holding the particles of the dry powder in an aggregated state is such that a patient""s breath, over a reasonable physiological range of inhalation flow rates is sufficient to deaggregate the powder contained in the receptacle into respirable particles. The deaggregated particles can penetrate via the patient""s breath into and deposit in the airways and/or deep lung with high efficiency.
The invention has many advantages. For example, pulmonary delivery provides on-demand treatment without the inconvenience of injections. Selective delivery of a medicament to the central nervous system can be obtained in a time frame not available with other administration routes, in particular conventional oral regimens. Thus, an effective dose can be delivered to the site of action on the xe2x80x9cfirst passxe2x80x9d of the medicament in the circulatory system. By practicing the invention, relief is available to symptomatic patients in a time frame during which conventional oral therapies would still be traveling to the site of action. The reduced doses employed in the methods of the invention result in a plasma drug level which is equivalent to that obtained with the oral dose. Blood plasma levels approaching those observed with intravenous administration can be obtained. Dose advantages over other routes of administration, e.g., intramuscular, subcutaneous, intra-peritoneal, buccal, rectal and nasal, also can be obtained. Furthermore, a therapeutic amount of the drug can be delivered to the pulmonary system in one or a small number of steps or breaths.